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OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence

OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence
OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence
Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic Abs, but especially anti-CD27, demonstrated synergy with anti-PD-L1 by enhancing CD8(+) T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergized by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bet(high) cells within the exhausted population. However, in the presence of persistent Ag, the CD8(+) T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated costimulation can synergize with coinhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations, but at the expense of losing precursor cells required to maintain a response.
0022-1767
125-133
Buchan, S.
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Manzo, T.
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Flutter, B.
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Rogel, A.
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Edwards, N.
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Zhang, L.
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Sivakumaran, S.
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Ghorashian, S.
f0f52658-beb1-43c3-aef2-05e5024ede4c
Carpenter, B.
860f0326-4ef5-44d3-ad27-99633413ecff
Bennett, C.L.
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Freeman, G.J.
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Sykes, M.
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Croft, M.
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Al-Shamkhani, A.
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Chakraverty, R.
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Buchan, S.
9ade187d-f127-45de-ad90-9d544d64718a
Manzo, T.
19122cf2-1f75-4dfc-8318-f23d116c21b3
Flutter, B.
97b9c93f-72dd-4103-b29d-7564af8d0808
Rogel, A.
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Edwards, N.
0ee9d704-3e71-465d-a12d-0e72bdcc3ca3
Zhang, L.
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Sivakumaran, S.
a4794741-b4e0-4484-b936-9390cb6db434
Ghorashian, S.
f0f52658-beb1-43c3-aef2-05e5024ede4c
Carpenter, B.
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Bennett, C.L.
d9ca665b-9f65-4851-8962-d1f6c6d315f8
Freeman, G.J.
da388e52-3d1b-4362-8f83-5c03f23cc250
Sykes, M.
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Croft, M.
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Al-Shamkhani, A.
0a40b3ce-9d71-4d41-9369-7212f0a84504
Chakraverty, R.
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Buchan, S., Manzo, T., Flutter, B., Rogel, A., Edwards, N., Zhang, L., Sivakumaran, S., Ghorashian, S., Carpenter, B., Bennett, C.L., Freeman, G.J., Sykes, M., Croft, M., Al-Shamkhani, A. and Chakraverty, R. (2015) OX40- and CD27-mmediated costimulation synergizes with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. Journal of Immunology, 194 (1), 125-133. (doi:10.4049/jimmunol.1401644). (PMID:25404365)

Record type: Article

Abstract

Exhaustion of chronically stimulated CD8(+) T cells is a significant obstacle to immune control of chronic infections or tumors. Although coinhibitory checkpoint blockade with anti-programmed death ligand 1 (PD-L1) Ab can restore functions to exhausted T cell populations, recovery is often incomplete and dependent upon the pool size of a quiescent T-bet(high) subset that expresses lower levels of PD-1. In a model in which unhelped, HY-specific CD8(+) T cells gradually lose function following transfer to male bone marrow transplantation recipients, we have explored the effect of shifting the balance away from coinhibition and toward costimulation by combining anti-PD-L1 with agonistic Abs to the TNFR superfamily members, OX40 and CD27. Several weeks following T cell transfer, both agonistic Abs, but especially anti-CD27, demonstrated synergy with anti-PD-L1 by enhancing CD8(+) T cell proliferation and effector cytokine generation. Anti-CD27 and anti-PD-L1 synergized by downregulating the expression of multiple quiescence-related genes concomitant with a reduced frequency of T-bet(high) cells within the exhausted population. However, in the presence of persistent Ag, the CD8(+) T cell response was not sustained and the overall size of the effector cytokine-producing pool eventually contracted to levels below that of controls. Thus, CD27-mediated costimulation can synergize with coinhibitory checkpoint blockade to switch off molecular programs for quiescence in exhausted T cell populations, but at the expense of losing precursor cells required to maintain a response.

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Accepted/In Press date: 22 October 2014
e-pub ahead of print date: 17 November 2014
Published date: 1 January 2015
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 390018
URI: https://eprints.soton.ac.uk/id/eprint/390018
ISSN: 0022-1767
PURE UUID: d1acf64d-64e1-4eb7-9769-61f9b3722b54
ORCID for A. Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 17 Mar 2016 11:59
Last modified: 31 Jan 2019 01:37

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Contributors

Author: S. Buchan
Author: T. Manzo
Author: B. Flutter
Author: A. Rogel
Author: N. Edwards
Author: L. Zhang
Author: S. Sivakumaran
Author: S. Ghorashian
Author: B. Carpenter
Author: C.L. Bennett
Author: G.J. Freeman
Author: M. Sykes
Author: M. Croft
Author: A. Al-Shamkhani ORCID iD
Author: R. Chakraverty

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